Preparation method of benzhydryl s-oxopenicillanate

A technology of diphenylmethyl sulfoxide and aminopenicillanic acid, applied in the direction of organic chemistry and the like, can solve the problems of complex process route, long synthesis period, poor product quality, etc., and achieves good reaction selectivity and short reaction period , the effect of mild reaction conditions

Active Publication Date: 2013-04-17
JIANGXI FUSHINE PHARMA CO LTD
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In order to overcome the above defects such as complicated process route, complicated operation, poor product quality, low yield, long synthesis cycle, expensive catalyst and high-risk operation, the invention provides a kind of diphenylmethyl penicillane sulfoxide Preparation method, its synthetic route is as follows:

Method used

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  • Preparation method of benzhydryl s-oxopenicillanate
  • Preparation method of benzhydryl s-oxopenicillanate
  • Preparation method of benzhydryl s-oxopenicillanate

Examples

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example 1

[0038] Example 1: Preparation of penicillane sulfoxide acid (ⅳ)

[0039] Suck in 36% sulfuric acid (80kg) and 60L ethanol sequentially into the 500L reactor, and put in 45kg of 6-aminopenicillanic acid (ii). Temperature control -20°C~10°C Add 37% sulfuric acid (100kg) and 37% sodium nitrite aqueous solution (60kg) dropwise at the same time, then add 50% hypophosphorous acid aqueous solution (28kg) dropwise at temperature control -20°C~10°C, keep warm After 1-10 hours, extract with dichloromethane to obtain a dichloromethane solution of penicillanic acid (Ⅲ), with a purity of ≥90%. Add catalyst molybdenum acetylacetonate to the reaction kettle, and then add 50% hydrogen peroxide (45kg) dropwise at -15-10°C under temperature control. ), yield ≥ 90%, purity ≥ 95%.

example 2

[0040] Example 2: Preparation of benzhydryl penicillane sulfoxide (i)

[0041] Pump acetone (36kg) and dichloromethane (265kg) into the 500L reactor, put in penicillane sulfoxide acid (ⅳ) (30kg), put in benzophenone hydrazone (39kg) and pump in 1 % KI in water (11 kg). Temperature control-20-0℃, add peracetic acid (75kg) dropwise, keep warm for 1~5h, wash the organic phase with 100ml brine and 100ml sodium bicarbonate solution, evaporate to dryness under reduced pressure, add toluene (50kg), temperature control -20 After stirring at ~15°C for 3 hours, centrifuge and dry to obtain diphenylmethyl penicillane sulfoxide (48kg), with a yield of ≥72% and a content of ≥98%. Purity chart see figure 1 , the content is 99.67% after comparison with the standard product verified by the enterprise.

[0042]

[0043]

example 3

[0044] Example 3: Preparation of penicillane sulfoxide acid (ⅳ)

[0045] Suck in 20% sulfuric acid (144kg) and 60L ethanol sequentially into the 500L reactor, and put in 45kg of 6-aminopenicillanic acid (ii). Control temperature -20℃~10℃, add 15% sulfuric acid (98kg) and 35% sodium nitrite aqueous solution (45kg) dropwise at the same time, then add 40% hypophosphorous acid aqueous solution (38kg) dropwise at temperature control -20℃~10℃, keep warm 1~10h, extract with dichloromethane to obtain penicillanic acid (Ⅲ) dichloromethane solution, purity ≥ 90%. Add catalyst molybdenum acetylacetonate to the reaction kettle, then add 50% hydrogen peroxide (45kg) dropwise at -15-10°C under temperature control, after the addition is complete, keep warm for 0.5-5h, and centrifuge to obtain penicillane sulfoxide acid (ⅳ) (37.8kg ), yield ≥ 90%, purity ≥ 95%.

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Abstract

The invention provides a preparation method of benzhydryl s-oxopenicillanate, which comprises the following steps: reacting 6-aminopenicillanic acid to obtain a penicillanic acid (iii) solution; adding catalyst molybdenum acetopyruvate, and dropwisely adding oxydol while controlling the temperature; after the reaction finishes, centrifuging to obtain oxopenicillanic acid; and reacting to obtain the benzhydryl s-oxopenicillanate. The method provided by the invention has the following advantages: 1. simplified synthesis steps: the processes of bromination and reduction debromination are not adopted; 2. short reaction period: only three reaction steps are adopted, thereby greatly shortening the production period; 3. favorable reaction selectivity and high yield: the total yield of the three steps for preparing the benzhydryl s-oxopenicillanate is higher than 72%; 4. mild reaction conditions: the high-risk hydrogenation reaction is not needed; and 5. the separation of the product and the intermediates is simple to operate, the two intermediates in the benzhydryl s-oxopenicillanate synthesis route can be directly used for synthesizing the required compound without refinement, and the end product can be directly filtered and separated.

Description

technical field [0001] The invention relates to a preparation method of penicillane sulfoxide diphenylmethyl ester, an intermediate of tazobactam crude drug. Background technique [0002] The structural formula of diphenylmethyl penicillane sulfoxide is [0003] [0004] Diphenylmethyl penicillane sulfoxide [0005] Diphenylmethyl penicillane sulfoxide is a key intermediate necessary for ring expansion to obtain carbapenes and oxycephem cephalosporins-nuclei, and is also a novel β-lactamase inhibitor tazobactam Tazobactam is a broad-spectrum and efficient β-lactamase inhibitor developed by Dapeng Pharmaceutical Company in Japan. Because of its excellent application performance, small toxic and side effects, strong enzyme inhibitory activity and stability Highly characteristic, it was rated as the most promising β-lactamase inhibitor at the 30th International Chemotherapy Conference. [0006] According to literature reports, there are roughly the following four syntheti...

Claims

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Application Information

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IPC IPC(8): C07D499/86C07D499/08
Inventor 柴建华程荣武徐长青刘亚林许蓓珍李勇
Owner JIANGXI FUSHINE PHARMA CO LTD
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